Colloidal silver ingestion with copper and caeruloplasmin deficiency

Abstract

The copper concentration in serum can be affected by the presence of other trace elements such as silver. Low serum copper may result in decreased caeruloplasmin synthesis. We report the case of a 59-year-old woman, who was admitted to hospital with acute psychosis and who had been ingesting chronically, colloidal silver.

Case

A 59-year-old woman was admitted to the medical ward in this hospital with acute psychosis, impaired consciousness and delusional beliefs. For the previous eight months, she had been self-medicating with 15 oz (approximately 422 mL of variable concentration) per day of colloidal silver, which she believed to be an effective treatment for dermatitis. Her past medical history was unremarkable apart from fibromyalgia. Physical examination, including a detailed neurological examination, was normal. She was apyrexial. Organic causes for her psychosis were excluded by a normal computed tomography scan of her head. Liver function tests, urea and electrolytes, full blood count, C-reactive protein and thyroid function tests were all within normal limits.

The patient had elevated blood levels of circulating silver at 2552 nmol/L (limit <2.8 nmol/L) and a markedly elevated urinary excretion of silver at 615 nmol/L (<7.42 nmol/L). Other measurements (with reference ranges) were serum: selenium 0.53 μmol/L (0.89–1.65), zinc 12.0 μmol/L (10–18), copper 4.0 μmol/L (11–20) and caeruloplasmin 0.14 g/L (0.20–0.40); and 24-h urine excretion of copper 0.4 μmol (<0.9). The metals were determined by inductively coupled plasma mass spectrometry and caeruloplasmin by immunoassay.

Discussion

The chronic ingestion of colloidal silver by our patient markedly increased her blood concentration of silver (approximately 1000-fold) accompanied by a notable elevation in the urinary excretion of silver. The serum copper, caeruloplasmin and selenium concentrations were all significantly decreased; however, zinc was unaffected. We speculate that an interaction between metabolism of silver and copper was responsible for the considerable decrease in both serum copper and caeruloplasmin concentrations.

Silver is antagonistic to copper and has been shown experimentally to reduce the biosynthesis of caeruloplasmin. ¹ Normally, the injection of copper into copper-deficient rats will increase the synthesis of caeruloplasmin. ² Sugawara and Sugawara ³ have shown in an animal model that serum caeruloplasmin significantly decreased after the administration of silver nitrate. Low caeruloplasmin concentrations were accompanied by low copper concentrations. Whanger and Weswig ⁴ described the effects of metals on caeruloplasmin synthesis in a rat model, and showed that the magnitude of the antagonistic effect varied: silver>cadmium>molybdenum>zinc. ⁴ It has been suggested that these metals interfere with the utilization of copper in the biosynthesis of caeruloplasmin in the liver but the mechanism is not clear and may be due to inhibition of transcription or a post-transcriptional event. ¹ These metals, apart from molybdenum, are able to induce metallothionein-like proteins in the liver (and kidney) which bind copper, and effectively produce a functional deficiency of the metal and of caeruloplasmin. ^3,5 It has been also suggested that the reduced oxidase activity of caeruloplasmin in the liver, caused by silver, could be due to the leakage of silver–caeruloplasmin into the blood. ³

Silver has been also shown to act by means of inhibiting gastrointestinal divalent copper absorption. Lee et al. ⁶ demonstrated in competition experiments that silver monovalent ion (Ag⁺) inhibits the copper uptake. Ag⁺, which is isoelectric to Cu⁺, can be transported by human copper transporter 1 (hCtr1), a specific metal transporter, for which the monovalent copper is a preferred substrate. ⁶ Consistent with that observation, ascorbate treatment to reduce Cu²⁺ to Cu⁺ enhances copper uptake.

Additionally, the N-terminal regions of both human and yeast Ctr1 contain multiple methionine residues organized in copper-binding methionine motifs that were synthesized and determined to selectively bind Cu⁺ and Ag⁺, with no affinity for divalent metal ions. ⁷

This is the first case report illustrating significantly depressed copper and caeruloplasmin concentrations in a patient ingesting colloidal silver. Previously similar findings have been described in thermal injury patients receiving topical silver sulphadiazine cream for burns ^8,9 or 5% silver nitrate to treat mouth ulcers. ¹⁰ It was observed in these patients that large accumulations of silver were deposited in the liver, ⁸ in the cytoplasm of both epidermal cells and sweat glands, ⁹ and in mucosa of the lips, gingiva and cheeks. This was associated with significantly reduced serum copper and caeruloplasmin concentrations, but serum zinc concentrations were not significantly altered. These observations are consistent with those of Boosalis et al., ¹ who previously documented that topical treatment with sulphadiazine cream (hence silver ion) does not diminish the circulating concentrations of divalent cations such as zinc, in a rat model. ¹

Low serum copper and caeruloplasmin concentrations are associated with Wilson's disease; however, normal neurological examination and liver function tests made this an unlikely diagnosis in our patient. Moreover, her previous medical history was not suggestive of Wilson's disease. It is worth noting that copper and caeruloplasmin deficiency has previously been associated with the appearance of an abnormal mental state. ¹⁰ This patient was not known to have had any previous psychiatric disorders and the possibility of colloidal silver-induced copper deficiency remains the likely explanation for her acute psychosis.

The finding of a low serum selenium concentration in a patient with silver toxicity is consistent with a previous case report. ¹¹ In chronic systemic silver overload when excretory mechanisms become saturated, selenium serves as a major protective factor in precipitating the silver in the form of a highly insoluble silver selenide. ¹¹

During her hospital stay, this patient discontinued colloidal silver intake and after three weeks her urinary excretion of silver had fallen to 160 nmol/L (reference limit <7.42 nmol/L). She did not receive any trace element supplements. After the decrease in blood silver concentrations, copper and caeruloplasmin concentrations returned to normal: 11 μmol/L and 0.21 g/L, respectively. We conclude that her acute psychosis and low copper and caeruloplasmin concentrations were transient features secondary to silver toxicity.

DECLARATIONS

Competing interests: Not applicable.

Funding: Not applicable.

Ethical approval: Informed consent obtained from the patient.

Guarantor: KMS.

Contributorship: KMS has researched the literature and wrote the first draft of the manuscript. AT was involved in the discussion development and contributed to the specialized analytical aspect of it. Both authors reviewed and edited the manuscript and approved the final version of the manuscript.

Acknowledgement: We would like to thank Dr Linda Morgan, Dr Tony Hitch and Dr Pankaj Gupta for the guidance in this case report.